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U.S. Department of Health and Human Services

Drugs

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FDA Statement on the Results of the Women's Health Initiative (Posted 8/13/2002)

Women’s Health Initiative (WHI) Results Signal Need for Reassessment of Risks and Benefits of Conjugated Equine Estrogens/medroxyprogesterone Acetate (Prempro) in Postmenopausal Women

On July 9, 2002, the National Heart, Lung, and Blood Institute (NHLBI) announced that it was stopping the combination conjugated equine estrogen/medroxyprogesterone acetate (Prempro) study being performed as a part of the Women’s Health Initiative (WHI). This study was conducted to assess whether long term use of Prempro would reduce the risk of coronary heart disease (CHD) in postmenopausal women. It was stopped early (after an average of 5.2 years on study) because the overall health risks of Prempro, particularly for invasive breast cancer and CHD, exceeded the benefits of the drug, which included a lower rate of fractures and a reduction in the risk of colorectal cancer.

No estrogen or estrogen/progestin combination product has been approved by the FDA for prevention of CHD or other cardiovascular disease. In recent years, based on epidemiologic data that suggested a possible cardiovascular benefit, estrogens or combination products have been prescribed for postmenopausal women specifically for preventing CHD. The WHI study was initiated to evaluate the long-term benefits and risks of therapy with estrogen or combination products in postmenopausal women. The WHI now establishes that Prempro should not be prescribed to postmenopausal women for cardiovascular protection. Another WHI study is assessing whether long term use of an estrogen preparation (Premarin), in postmenopausal women who do not have a uterus, will decrease the risk of CHD in that population. This study is still ongoing. Until this study is completed, long-term use of estrogen products to prevent cardiovascular disease should be considered investigational.

Prempro is currently FDA-approved for: 1) treatment of moderate-to-severe vasomotor symptoms associated with the menopause 2) treatment of vulvar and vaginal atrophy, and 3) prevention of postmenopausal osteoporosis. Estrogen products are not FDA-approved for prevention of cognitive deficits. Although the recently stopped WHI study did not target symptomatic women or those at risk for osteoporotic complications, the study does provide data on the long-term risks of Prempro in postmenopausal women. The increased risks of breast cancer and thromboembolic disease associated with estrogen and combination estrogen/progestin had previously been known or suspected. The increased risk of cardiovascular disease, including heart attack and stroke, in healthy women, is new information. Women taking Prempro or other combination estrogen/progestin therapy should consult with their healthcare provider about the relevance of this new information to their treatment. The decision whether to continue therapy must be individualized, taking into account the known benefits and risks of therapy, as well as alternative treatments. As is true for all medications, the lowest effective dose should be sought.

Because of differences in estrogenic potency and product composition, the extent that the new findings about risks are generalizable to other combination estrogen/progrestin products is not known. The long-term risks of lower doses of Prempro were not evaluated in the WHI trial.

The Department of Health and Human Services will host public sessions on this issue in the fall. More information on this will follow. Consideration will be given to the extent to which the WHI results might be extrapolated to other combination estrogen/progestin products and doses, an assessment of known benefits for approved indications in the light of these new data, and the WHI's implications for future clinical trials of hormonal therapy.